Compound heterozygous mutation in MTHFR gene lead to chronic cerebral venous thrombosis: one case report

doi:10.3969/j.issn.1672-6731.2025.06.010

Chinese Journal of Contemporary Neurology and Neurosurgery ›› 2025, Vol. 25 ›› Issue (6): 517-522. doi: 10.3969/j.issn.1672-6731.2025.06.010

• Cerebral Venous Syetem Diseases • Previous Articles Next Articles

Compound heterozygous mutation in MTHFR gene lead to chronic cerebral venous thrombosis: one case report

Xuan-yue YU¹, Ke-xin LIU², Tie-ping FAN¹, Shu-min LI¹, Xin-tian LIANG³, Yi LIU¹^,*()

1. Department of Neurology, Central Hospital of Dalian University of Technology, Dalian 116033, Liaoning, China
2. Grade 2023, The First Clinical College of China Medical University, Shenyang 110122, Liaoning, China
3. Grade 2022, Graduate School of Dalian Medical University, Dalian 116044, Liaoning, China

Received:2025-03-19 Online:2025-06-25 Published:2025-07-04
Contact: Yi LIU
Supported by:
the National Natural Science Foundation of China for Young Scientists(81200915); Liaoning "Xingliao Talents Plan" Project(XLYC1807083); Dalian Science and Technology Innovation for Public Welfare Plan Project in Liaoning(2024JJ13PT051); Dalian Science and Technology Innovation for Public Welfare Plan Project in Liaoning(2021JJ13SN64); Dalian Municipal Central Hospital "Summit Plan" Project in Liaoning(2024ZZ041)

MTHFR基因复合杂合突变相关慢性脑静脉血栓形成一例

余璇玥¹, 刘可心², 范铁平¹, 李淑敏¹, 梁心田³, 刘毅¹^,*()

1. 116033 大连理工大学附属中心医院神经内科
2. 110122 沈阳，中国医科大学第一临床学院 2023 级
3. 116044 大连医科大学研究生院 2022 级

通讯作者: 刘毅
作者简介:
余璇玥与刘可心对本文有同等贡献

YU Xuan-yue and LIU Ke-xin contributed equally to the article
基金资助:
国家自然科学基金青年科学基金资助项目(81200915); 辽宁省“兴辽英才计划”项目(XLYC1807083); 辽宁省大连市科技创新惠民计划项目(2024JJ13PT051); 辽宁省大连市科技创新惠民计划项目(2021JJ13SN64); 辽宁省大连市中心医院“登峰计划”项目(2024ZZ041)

Abstract

Abstract:

Objective To report one case of chronic cerebral venous thrombosis (CVT) caused by compound heterozygous mutation in MTHFR gene, and to investigate the association between compound heterozygous mutation in MTHFR gene and chronic CVT as well as its pathophysiology mechanism. Methods and Results A 27-year-old male patient presented to the hospital with sudden onset headache. Imaging findings showed chronic thrombosis of the left superior sagittal sinus, inferior sagittal sinus, straight sinus, transverse sinus and confluence of sinus, and laboratory tests revealed hyperhomocysteinemia (homocysteine > 100 μmol/L). Genetic testing showed that the patient had a compound heterozygous mutation of MTHFR gene c. 325C > G (p. Arg109Gly) and c. 277C > T (p. Arg93Ter), and the mother also carried the c. 277C > T (p. Arg93Ter) heterozygous mutation, suggesting a familial predisposition. The clinical diagnosis was chronic CVT caused by a compound heterozygous mutation in MTHFR gene. Following anticoagulation therapy combined with folate acid and vitamin B supplementation, symptoms improved, but homocysteine level remained elevated. Conclusions This paper first reports the association of MTHFR gene c.325C > G (p.Arg109Gly) and c.277C > T (p.Arg93Ter) compound heterozygous mutation with CVT. Compound heterozygous mutation in MTHFR gene play an important role in the chronicity of thrombosis, and the necessity of genetic testing and individualized therapy for patients with hereditary thrombophilia should be emphasized.

Key words: Venous thrombosis, Cerebral veins, Chronic disease, Methylenetetrahydrofolate reductase (NADPH2), Genes, Mutation, Heterozygote, Hyperhomocysteinemia

摘要：

目的: 报道1例MTHFR基因复合杂合突变致慢性脑静脉血栓形成病例，探讨MTHFR基因复合杂合突变与慢性脑静脉血栓形成的关联及其病理生理学机制。方法与结果: 男性患者，27岁，因突发头痛就诊，CTV显示左侧上矢状窦、下矢状窦、直窦、横窦及窦汇血栓形成（慢性期）；实验室检查提示高同型半胱氨酸血症（同型半胱氨酸> 100 μmol/L）；基因检测显示MTHFR基因c.325C > G（p.Arg109Gly）及c.277C > T（p.Arg93Ter）复合杂合突变，其母携带MTHFR基因c.277C > T（p.Arg93Ter）杂合突变，提示家族遗传倾向。临床诊断为MTHFR基因复合杂合突变致慢性脑静脉血栓形成。经抗凝治疗联合叶酸、维生素B6和甲钴胺治疗后症状缓解，但同型半胱氨酸始终未降至正常水平。结论: 首次报道MTHFR基因c.325C > G（p.Arg109Gly）及c.277C > T（p.Arg93Ter）复合杂合突变与慢性脑静脉血栓形成的关联，MTHFR基因复合杂合突变在血栓慢性化过程中具有重要作用，对遗传性易栓症应强调基因检测与个性化治疗的重要性。

关键词: 静脉血栓形成, 脑静脉, 慢性病, 亚甲基四氢叶酸还原酶（NADPH）, 基因, 突变, 杂合子, 高同种半胱氨酸血症

Xuan-yue YU, Ke-xin LIU, Tie-ping FAN, Shu-min LI, Xin-tian LIANG, Yi LIU. Compound heterozygous mutation in MTHFR gene lead to chronic cerebral venous thrombosis: one case report[J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2025, 25(6): 517-522.

余璇玥, 刘可心, 范铁平, 李淑敏, 梁心田, 刘毅. MTHFR基因复合杂合突变相关慢性脑静脉血栓形成一例[J]. 中国现代神经疾病杂志, 2025, 25(6): 517-522.

/ / Recommend / Download Citations

URL: https://journal11.magtechjournal.com/cjcnn/EN/10.3969/j.issn.1672-6731.2025.06.010

https://journal11.magtechjournal.com/cjcnn/EN/Y2025/V25/I6/517

Figures/Tables 3

Figure 1 Head CTV findings Sagittal CTV showed thrombosis in the superior sagittal sinus (arrow indicates, Panel 1a). Coronal CTV showed thrombosis in the superior sagittal sinus (thick arrow indicates) and left transverse sinus (thin arrow indicates, Panel 1b).

Figure 2 MTHFR gene testing findings The patient had the MTHFR gene c. 325C > G (p. Arg109Gly) heterozygous mutation (arrow indicates, Panel 2a). The patient had the MTHFR gene c. 277C > T (p. Arg93Ter) heterozygous mutation (arrow indicates, Panel 2b). The mother of patient didn't carry the MTHFR gene c.325C > G (p.Arg109Gly) heterozygous mutation (Panel 2c). The mother of patient carried the MTHFR gene c.277C > T (p.Arg93Ter) heterozygous mutation (arrow indicates), indicating a familial aggregation pattern of this variant (Panel 2d).

Figure 3 Schematic diagram of Hcy metabolism pathway and gene mutation pathogenesis: MTHFR gene compound heterozygous mutation [c.325C > G (p.Arg109Gly) and c.277C > T (p.Arg93Ter)] impair MTHFR activity, blocking the conversion of 5, 10-MTHF to 5-MTHF, thereby disrupting Hcy remethylation and leading to Hcy accumulation. Elevated Hcy triggers oxidative stress, enhances platelet aggregation, increases blood viscosity, and coagulation dysregulation, ultimately contributing to the cerebral venous thrombosis.

References 23

1	Chatterjee B , Fatima F , Seth S , Sinha Roy S . Moderate elevation of homocysteine induces endothelial dysfunction through adaptive UPR activation and metabolic rewiring. Cells, 2024, 13: 214. doi: 10.3390/cells13030214
2	Han L , Miao Y , Zhao Y , Zhang X , Ma X , Du X , Kong W , Xu Q , Liu J , Dai K , Feng J , Wang X . The binding of autotaxin to integrins mediates hyperhomocysteinemia - potentiated platelet activation and thrombosis in mice and humans. Blood Adv, 2022, 6: 46- 61. doi: 10.1182/bloodadvances.2021004572
3	Liang C , Wang QS , Yang X , Zhu D , Sun Y , Niu N , Yao J , Dong BH , Jiang S , Tang LL , Lou J , Yu CJ , Shao Q , Wu MM , Zhang ZR . Homocysteine causes endothelial dysfunction via inflammatory factor - mediated activation of epithelial sodium channel (ENaC. Front Cell Dev Biol, 2021, 9: 672335. doi: 10.3389/fcell.2021.672335
4	Weile J , Kishore N , Sun S , Maaieh R , Verby M , Li R , Fotiadou I , Kitaygorodsky J , Wu Y , Holenstein A , Bürer C , Blomgren L , Yang S , Nussbaum R , Rozen R , Watkins D , Gebbia M , Kozich V , Garton M , Froese DS , Roth FP . Shifting landscapes of human MTHFR missense-variant effects. Am J Hum Genet, 2021, 108: 1283- 1300. doi: 10.1016/j.ajhg.2021.05.009
5	Siddiqi SM , Liu L , Du Y , Song Y , Chen P , Li S , He Q , Zhou Z , Xu J , Bai J , Wang B , Qin X , Mehmood A , Xiuqing L , Cheng X , Shi HP . Association of MTHFR C677T, MTHFRA1298C, and MTRRA66G gene polymorphisms with hyperhomocysteinemia and its modulation by the combined effect of vitamin B12 and folate in Chinese population with hypertension. J Nutr, 2025, 155: 1202- 1209. doi: 10.1016/j.tjnut.2024.09.003
6	Goyette P , Christensen B , Rosenblatt DS , Rozen R . Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR. Am J Hum Genet, 1996, 59: 1268- 1275.
7	Zhang M , Shi B , Zhao M . Cerebral venous thrombosis with hyperhomocysteinemia due to loss of heterozygosity at methylenetetrahydrofolate reductase (MTHFR) locus: a case report. BMC Neurol, 2023, 23: 154. doi: 10.1186/s12883-023-03200-y
8	Jakubowski H , Boers GH , Strauss KA . Mutations in cystathionine beta - synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans. FASEB J, 2008, 22: 4071- 4076. doi: 10.1096/fj.08-112086
9	Shahzad K , Hai A , Ahmed A , Kizilbash N , Alruwaili J . A structured-based model for the decreased activity of Ala222Val and Glu429Ala methylenetetrahydrofolate reductase (MTHFR) mutants. Bioinformation, 2013, 9: 929- 936. doi: 10.6026/97320630009929
10	Raghubeer S , Matsha TE . Methylenetetrahydrofolate (MTHFR), the one-carbon cycle, and cardiovascular risks. Nutrients, 2021, 13: 4562. doi: 10.3390/nu13124562
11	Alluri RV , Mohan V , Komandur S , Chawda K , Chaudhuri JR , Hasan Q . MTHFR C677T gene mutation as a risk factor for arterial stroke: a hospital based study. Eur J Neurol, 2005, 12: 40- 44. doi: 10.1111/j.1468-1331.2004.00938.x
12	Litvinov RI , Peshkova AD , Le Minh G , Khaertdinov NN , Evtugina NG , Sitdikova GF , Weisel JW . Effects of hyperhomocysteinemia on the platelet - driven contraction of blood clots. Metabolites, 2021, 11: 354. doi: 10.3390/metabo11060354
13	Kartal Ozer N , Taha S , Azzi A . Homocysteine induces DNA synthesis and proliferation of vascular smooth muscle cells by interfering with MAPK kinase pathway. Biofactors, 2005, 24 (1-4): 193- 199. doi: 10.1002/biof.5520240123
14	Loscalzo J . Homocysteine-mediated thrombosis and angiostasis in vascular pathobiology. J Clin Invest, 2009, 119: 3203- 3205.
15	Alvarez SI , Ollero EB , Llinares Sanjuan FM , Martínez FL , Calvo Martín MT . A deep vein thrombosis caused by 20209C > T mutation in homozygosis of the prothrombin gene in a Caucasian patient. Biochem Med (Zagreb), 2014, 24: 159- 166.
16	Zhang L , Sun L , Wei T . Correlation between MTHFR gene polymorphism and homocysteine levels for prognosis in patients with pregnancy - induced hypertension. Am J Transl Res, 2021, 13: 8253- 8261.
17	Tan H , Shi C , Jiang X , Lavelle M , Yu C , Yang X , Wang H . Hyperhomocysteinemia promotes vascular remodeling in vein graph in mice. Front Biosci (Landmark Ed), 2014, 19: 958- 966. doi: 10.2741/4260
18	Martinelli I , Battaglioli T , Pedotti P , Cattaneo M , Mannucci PM . Hyperhomocysteinemia in cerebral vein thrombosis. Blood, 2003, 102: 1363- 1366. doi: 10.1182/blood-2003-02-0443
19	Nagele P , Zeugswetter B , Wiener C , Burger H , Hüpfl M , Mittlböck M , Födinger M . Influence of methylenetetrahydrofolate reductase gene polymorphisms on homocysteine concentrations after nitrous oxide anesthesia. Anesthesiology, 2008, 109: 36- 43. doi: 10.1097/ALN.0b013e318178820b
20	Huang LW , Li LL , Li J , Chen XR , Yu M . Association of the methylenetetrahydrofolate reductase (MTHFR) gene variant C677T with serum homocysteine levels and the severity of ischaemic stroke: a case-control study in the southwest of China. J Int Med Res, 2022, 50: 1- 14.
21	Feng W , Zhang Y , Pan Y , Zhang Y , Liu M , Huang Y , Xiao Y , Mo W , Jiao J , Wang X , Tian D , Yang L , Ma Y . Association of three missense mutations in the homocysteine-related MTHFR and MTRR gene with risk of polycystic ovary syndrome in Southern Chinese women. Reprod Biol Endocrinol, 2021, 19: 5. doi: 10.1186/s12958-020-00688-8
22	Franchini M , Krampera M , Veneri D . Deep vein thrombosis after orthopedic surgery in a patient with type 1 von Willebrand disease and mutations in the MTHFR and beta-fibrinogen genes. Thromb Haemost, 2003, 90: 963- 964. doi: 10.1055/s-0037-1613499
23	Miranda - Vilela AL . Role of polymorphisms in factor V (FV Leiden), prothrombin, plasminogen activator inhibitor type - 1 (PAI - 1), methylenetetrahydrofolate reductase (MTHFR) and cystathionine β - synthase (CBS) genes as risk factors for thrombophilias. Mini Rev Med Chem, 2012, 12: 997- 1006. doi: 10.2174/138955712802762338

[1]	Jian-gang DUAN, Bao-ying SONG. Progress and prospect of glucocorticoids therapy for severe cerebral venous thrombosis [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2025, 25(6): 459-463.
[2]	Jia-hao ZHANG, Lei GENG, Zhi-tao XIAO, Xing CHEN, Xiang-yu CAO. Advances in the study methods of cerebral venous sinus hemodynamics [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2025, 25(6): 464-469.
[3]	Yu-shuang RUAN, Zi-kang DONG, Zhi FANG, Yuan-peng XIA. Inflammatory mechanisms and therapeutic targets in cerebral venous system diseases [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2025, 25(6): 470-476.
[4]	Ye LANG, Meng-fei ZHONG, Zong-en GAO. Progress on anticoagulation therapy and mechanical thrombectomy for cerebral venous thrombosis [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2025, 25(6): 477-482.
[5]	Hong-yan DING, Ya-nan XIE, Qiang DONG. Analysis of influencing factors of increased intracranial pressure in patients with cerebral venous thrombosis [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2025, 25(6): 483-488.
[6]	Qiu-ju LIAO, Xiao-yi YANG, Yi ZHAO, Li SU. Clinical characteristics of cerebral venous thrombosis in patients with systemic lupus erythematosus [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2025, 25(6): 503-508.
[7]	Hou-lin LAI, Jing-kai LI, Na TANG, Jian-gang DUAN. Severe cerebral venous thrombosis initially presenting as puerperium psychiatric and behavioral symptoms: one case report [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2025, 25(6): 509-516.
[8]	HUANG Zhan, ZHU Ming-fang, MENG Qi, TAN Lei-lei, ZHANG Jie-wen, HUANG Yue. Protein C and protein S deficiency associated cerebral venous thrombosis: one case report [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2025, 25(6): 523-529.
[9]	DING Le, SHI Miao, XUE Xiu-yun, ZHANG Quan, LIU Zhi-qin. Anemia-induced recurrent cerebral venous thrombosis: one case report and literature review [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2025, 25(6): 530-537.
[10]	Zhen LI, Peng-fei SONG, Rui-ze ZHU, Shan JIANG, Shi-wen CAO, Jin-hua YU, Zhi-feng SHI. Prediction of genetic status and grading in glioma based on fusion of macro - and micro-imaging features [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2025, 25(3): 165-174.
[11]	Jing-jing GE, Chen-chen KONG, Chuan ZHAO, Jun-ping ZHANG. Research advances on chemotherapy and targeted therapy of pediatric-type low-grade glioma [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2024, 24(9): 706-711.
[12]	Ji-wei JIANG, Shi-rui JIANG, Wen-yi LI, Min ZHAO, Hui-ying ZHANG, Jun XU. Dynamic mutations of RFC1-related to multiple system atrophy: one case report [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2024, 24(9): 772-776.
[13]	Li LIN, Zhen-zhen CUI, Fan HE, Xiao-ling ZHAO, Dan-qun JIN, Bin YANG. Analysis of genetic characteristics in four children with atypical Rett syndrome and developmental epileptic encephalopathy caused by IQSEC2 gene variation [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2024, 24(8): 674-683.
[14]	Yue-xin MEI, Xin-ran CHEN, Hong-bing CHEN. Endovascular treatment of acute straight sinus thrombosis: one case report [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2024, 24(8): 684-688.
[15]	Yu-qing YUAN, Qing-qing ZHAN, Liang XIE. Type Ⅱ Alexander's disease: one case report [J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2024, 24(6): 502-506.

Please choose a citation manager

Content to export